Macrophage involvement in the pathological evolution of ulcerative colitis-associated colon cancer and progress of related traditional Chinese medicine drug interventions

Intestinal macrophages are essential players in intestinal inflammation and intestinal immune homeostasis.Intestinal macrophages have the ability to polarize into two distinct phenotypes based on various environmental signals.These phenotypes include the typically activated pro-inflammatory M1 phenotype and the alternatively activated anti-inflammatory M2 phenotype.Under normal circumstances,intestinal macrophages prevent inflammatory damage to the gut.However,when genetic and environmental factors influence the polarization of intestinal macrophages,it can lead to an imbalance in M1/M2 macrophage activation and subsequently an imbalance in the control of intestinal inflammation.It transforms physiological inflammation into pathological intestinal damage.In patients with ulcerative colitis-associated cancer(UC-CRC),intestinal inflammatory disorders are closely associated with intestinal M1/M2 macrophage polarization imbalance.Consequently,restoring the polarization equilibrium of M1/M2 macrophages might be an evidence of traditional Chinese medicine in the treatment of UC-CRC,the pivotal role o effective measure to prevent and treat UC-CRC.This paper aims to examine the clinicalf macrophage polarization in UC-CRC pathogenesis,and the potential mechanisms of traditional Chinese medicine in regulating macrophage polarization to treat UC-CRC.Our goal is to provide novel insights into the clinical practice,basic research,and drug development of UC-CRC.

Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.

Status of colitis-associated cancer in ulcerative colitis

Surgical therapy for ulcerative colitis(UC) depends on the medical therapy administered for the patient's condition. UC is a benign disease. However, it has been reported that the rare cases of cancer in UC patients are increasing, and such cases have a worse prognosis. Recently, surgical therapy has greatly changed, there has been quite an increase in the number of UC patients with high-grade dysplasia and/or cancer. These lesions are known as colitis-associated cancer(CAC). The relationship between inflammation and tumorigenesis is well-established, and in the last decade, a great deal of supporting evidence has been obtained from genetic, pharmacological, and epidemiological studies. Inflammatory bowel disease, especially UC, is an important risk factor for the development of colon cancer. We should determine the risk factors for UC patients with cancer based on a large body of data, and we should attempt to prevent the increase in the number of such patients using these newly identified risk factors in the near future. Actively introducing the surgical treatment in addition to medical treatment should be considered. Several physicians should analyze UC from their unique perspectives in order to establish new clinically relevant diagnostic and treatment methods in the future. This article discusses CAC, including its etiology, mechanism, diagnosis, and treatment in UC patients.

Landscape of cell heterogeneity and evolutionary trajectory in ulcerative colitis-associated colon cancer revealed by single-cell RNA sequencing

Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at the single-cell level.Methods:Fresh samples of tumor tissues and adjacent UC tissues from a CAC patient with pT3N1M0 stage cancer were examined by single-cell RNA sequencing(scRNA-seq).Data from The Cancer Genome Atlas(TCGA)and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with patient prognosis.Results:Ultimately,4,777 single-cell transcriptomes(1,220 genes per cell)were examined,of which 2,250(47%)and 2,527(53%)originated from tumor and adjacent UC tissues,respectively.We defined the composition of cancer-associated stromal cells and identified six cell clusters,including myeloid,T and B cells,fibroblasts,endothelial and epithelial cells.Notable pathways and transcription factors involved in these cell clusters were analyzed and described.Moreover,the precise cellular composition and developmental trajectory from UC to UCassociated colon cancer were graphed,and it was predicted that CD74,CLCA1,and DPEP1 played a potential role in disease progression.Conclusions:scRNA-seq technology revealed intra-tumor cell heterogeneity in UC-associated colon cancer,and might provide a promising direction to identify novel potential therapeutic targets in the evolution from UC to CAC.

Clinical usefulness of endoscopic ultrasonography for the evaluation of ulcerative colitis-associated tumors

AIM:To evaluate the clinical usefulness of endoscopic ultrasonography(EUS) for the diagnosis of the invasion depth of ulcerative colitis-associated tumors.METHODS:The study group comprised 13 patients with 16 ulcerative colitis(UC)-associated tumors for which the depth of invasion was preoperatively estimated by EUS.The lesions were then resected endoscopically or by surgical colectomy and were examined histopathologically.The mean age of the subjects was 48.2 ± 17.1 years,and the mean duration of UC was 15.8 ± 8.3 years.Two lesions were treated by endoscopic resection and the other 14 lesions by surgical colectomy.The depth of invasion of UCassociated tumors was estimated by EUS using an ultrasonic probe and was evaluated on the basis of the deepest layer with narrowing or rupture of the colonic wall.RESULTS:The diagnosis of UC-associated tumors by EUS was carcinoma for 13 lesions and dysplasia for 3 lesions.The invasion depth of the carcinomas was intramucosal for 8 lesions,submucosal for 2,the muscularis propria for 2,and subserosal for 1.Eleven(69%) of the 16 lesions arose in the rectum.The macroscopic appearance was the laterally spreading tumor-non-granular type for 4 lesions,sessile type for 4,laterally spreading tumor-granular type for 3,semipedunculated type(Isp) for 2,type 1 for 2,and type 3 for 1.The depth of invasion was correctly estimated by EUS for 15 lesions(94%) but was misdiagnosed as intramucosal for 1 carcinoma with high-grade submucosal invasion.The 2 lesions treated by endoscopic resection were intramucosal carcinoma and dysplasia,and both were diagnosed as intramucosal lesions by EUS.CONCLUSION:EUS provides a good estimation of the invasion depth of UC-associated tumors and may thus facilitate the selection of treatment.

Copy number variations are progressively associated with the pathogenesis of colorectal cancer in ulcerative colitis

AIM: To evaluate the association of known copy number variations(CNVs) in ulcerative colitis(UC) progressing to colorectal cancer.METHODS: Microsatellite instability analysis using the National Cancer Institute's panel of markers, and CNV association studies using Agilent 2 × 105 k arrays were done in tissue samples from four patient groups with UC: those at low risk(LR) or high risk of developing colorectal cancer, those with premalignant dysplastic lesions, and those with colitis-associated colorectal cancer(CAC). DNA from tissue samples of these groups were independently hybridized on arrays and analyzed. The data obtained were further subjected to downstream bioinformatics enrichment analysis to examine the correlation with CAC progression.RESULTS: Microarray analysis highlighted a progressive increase in the total number of CNVs [LR(n = 178) vs CAC(n = 958), 5.3-fold], gains and losses [LR(n = 37 and 141) vs CAC(n = 495 and 463), 13.4- and 3.3-fold, respectively], size [LR(964.2 kb) vs CAC(10540 kb), 10.9-fold] and the number of genes in such regions [LR(n = 119) vs CAC(n = 455), 3.8-fold]. Chromosomewise analysis of CNVs also showed an increase in the number of CNVs across each chromosome. There were 38 genes common to all four groups in the study; 13 of these were common to cancer genes from the Genetic Disease Association dataset. The gene set enrichment analysis and ontology analysis highlighted many cancerassociated genes. All the samples in the different groupswere microsatellite stable.CONCLUSION: Increasing numbers of CNVs are associated with the progression of UC to CAC, and warrant further detailed exploration.

Risk for colorectal cancer in ulcerative colitis:Changes,causes and management strategies

The risk of colorectal cancer for any patient with ulcer-ative colitis is known to be elevated, and is estimated to be 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. Risk factors for cancer in-clude extent and duration of ulcerative colitis, primary sclerosing cholangitis, a family history of sporadic colorectal cancer, severity of histologic bowel inflam-mation, and in some studies, young age at onset of colitis. In this review, the authors discuss recent epide-miological trends and causes for the observed chang-es. Population-based studies published within the past 5 years suggest that this risk has decreased over time, despite the low frequency of colectomies. The crude annual incidence rate of colorectal cancer in ulcerative colitis ranges from approximately 0.06% to 0.16% with a relative risk of 1.0-2.75. The exact mechanism for this change is unknown; it may partly be explained by the more widespread use of maintenance therapy and surveillance colonoscopy.

Screening of differentially expressed microRNA in ulcerative colitis related colorectal cancer

Objective:To investigate the differential expression of microRNA(miRNA)in colon between ulcerative colitis(UC)and ulcerative colitis related colorectal cancer(UCRCC).Methods:An UC mouse model was built by dextran sodium sulfate,and an UCRCC mouse model by dextran sodium sulfate and 1,2-diformylhydrazine.RNAs were extracted from the colon,purified and hybridized with fluorescence-labeled miRNA oligonucleotide gene chip.Real-time fluorescence quantitative PCR was used to verity the expression variation of miRNA.SAM was employed for the data analysis.Results:The up-regulated miRNA in colon cancer included has-miR-194,hasmiR-215,has-miR-93,has-miR-192,has-miR-92a,has-miR-29b,and has-miR-20a(median false discovery rate<5%),while the down-regulated miRNAs were has-miR-1231,has-miR-195,has-miR-143,and has-miR-145(median false discovery rate<5%).Conclusions:Significant differential expression of miRNA was found between the UC mouse and UCRCC mouse,which may be related to the onset,erosion and transfer of colorectal cancer.

Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer

AIM: To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer.

Interleukin-34 deficiency aggravates development of colitis and colitis-associated cancer in mice

BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acute colitis,in a wound healing model and in colitis-associated cancer in IL-34-deficient mice.METHODS Colitis was induced by administration of dextran sodium sulfate(DSS),and carcinogenesis was induced by azoxymethane(AOM).Whether the impact of IL-34 on colitis was dependent on macrophages was validated by depletion of macrophages in a murine model.The association between IL-34 expression and epithelial proliferation was studied in patients with active UC.RESULTS IL-34 deficiency aggravated murine colitis in acute colitis and in wound healing phase.The effect of IL-34 on experimental colitis was not dependent on macrophage differentiation and polarization.IL-34-deficient mice developed more tumors than wild-type mice following administration of AOM and DSS.No significant difference was shown in degree of cellular differentiation in tumors between wild-type and IL-34-deficient mice.IL-34 was dramatically increased in the active UC patients as previously reported.More importantly,expression of IL-34 was positively correlated with epithelial cell proliferation in patients with UC.CONCLUSION IL-34 deficiency exacerbates colonic inflammation and accelerates colitis-associated carcinogenesis in mice.It might be served as a potential therapeutic target in UC.

Colitis-associated colon cancer:Is it in your genes?

Colitis-associated colorectal cancer(CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease(IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which predispose them to CA-CRC development, although these loci have proven difficult to identify in human genomewide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic predisposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.

Lactobacillus bulgaricus inhibits colitis-associated cancer via a negative regulation of intestinal inflammation in azoxymethane/dextran sodium sulfate model

BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC.Recently,numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses.Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC,however little is known about their role in CAC.AIM To investigate the effect of the probiotic Lactobacillus bulgaricus(L.bulgaricus)during the development of an experimental model of colitis associated colon cancer(CAC).METHODS C57BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg),followed by three cycles of sodium dextran sulphate diluted in water(5%w/v).Probiotic group received daily L.bulgaricus.Intestinal inflammation was determined by scoring clinical signs.Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits.The level of significance was set at P<0.05.Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.RESULTS L.bulgaricus treatment inhibited of total tumor volume and mean size of tumors.In addition,the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6,TNF-α,IL-17,IL-23 and IL-1β.CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC.L.bulgaricus regulates the inflammatory response and preventing CAC.

Ulcerative colitis: From inflammation to cancer. Do estrogen receptors have a role?

Ulcerative colitis(UC) is a condition at increased risk for colorectal carcinoma(CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors(extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogenreceptors(ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anticarcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.

Fifteen-year-old colon cancer patient with a 10-year history of ulcerative colitis

Inflammatory bowel disease (IBD) is regarded as one of the risk factors for colorectal cancer, and early detection of cancer in these patients may be difficult, especially in pediatric patients. Prognosis of pediatric colorectal cancer is known to be poor, because of delayed diagnosis and unfavorable differentiation. We report a case of a pediatric patient with a 10-year history of ulcerative colitis who was diagnosed with sigmoid colon cancer when he was 15 years old. He underwent proctocolectomy with ileal pouch anal anastomosis. Postoperative pathological examination of the tumor revealed adenocarcinoma. The pericolic tissue layer was infiltrated, but metastases were not found in either of the two lymph nodes. Children with a long history of predisposing factors such as IBD need particular attention to the possibility of colorectal cancer. Early diagnosis through regular screening with colonoscopy is one of the most important critical factors for a good prognosis.

Update and latest advances in mechanisms and management of colitis-associated colorectal cancer

Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,including ulcerative colitis and Crohn’s disease,are known to have an increased risk of developing CAC.Although the incidence of CAC has significantly decreased over the past few decades,individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer,and the incidence of CAC increases with duration.Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC.CAC has been shown to progress from colitis to dysplasia and finally to carcinoma.Accumulating evidence suggests that multiple immune-mediated pathways,DNA damage pathways,and pathogens are involved in the pathogenesis of CAC.Over the past decade,there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients.Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers.It is generally recommended that CAC patients undergo endoscopic removal or colectomy.This review summarizes the current understanding of CAC,particularly its epidemiology,mechanisms,and management.It focuses on the mechanisms that contribute to the development of CAC,covering advances in genomics,immunology,and the microbiome;presents evidence for management strategies,including endoscopy and colectomy;and discusses new strategies to interfere with the process and development of CAC.These scientific findings will pave the way for the management of CAC in the near future.

TNF inhibitors to treat ulcerative colitis in a metastatic breast cancer patient:A case report and literature review

Adalimumab (ADA) is a tumor necrosis factor (TNF) inhibitor, used for the treatment of inflammatory bowel disease. Previous studies have reported an increased risk of cancer following exposure to TNF inhibitors, but little has been reported for patients with cancer receiving TNF-inhibitor treatment. We present a female patient with metastatic breast cancer and ulcerative colitis (UC) who was treated with ADA. A 54-year-old African American female with a past history of left-sided breast cancer (BC) diagnosed at age 30 was initially treated with left-breast lumpectomy, axillary dissection, followed by chemotherapy and radiation therapy. Years after initial diagnosis, she developed recurrent, bilateral BC and had bilateral mastectomy. Subsequent restaging computed tomography (CT) scan demonstrated distant metastases to the bone and lymph nodes. Three years into her treatment of metastatic breast cancer, she was diagnosed with UC by colonoscopy. Her UC was not controlled for 5 mo with 5-aminosalicylates. Subcutaneous ADA was started and resulted in dramatic improvement of UC. Four months after starting ADA, along with ongoing chemotherapy, restaging CT scan showed resolution of the previously seen metastatic lymph nodes. Bone scan and follow-up positron emission tomography/CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on ADA. While TNF-&#x003b1; inhibitors could theoretically promote further metastases in patients with prior cancer, this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after ADA initiation for UC.

Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer:Impact of rs10889677 variant and buparlisib in colitis-associated cancer

BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal cancer(CRC)with colitisassociated cancer(CAC).PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes.Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.METHODS Genomic DNA from 32 colonic samples,including CAC(n=7),UC(n=10)and CRC(n=15),was sequenced for the rs10889677 mutation.The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector.The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line.CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium,then buparlisib was administered after 14 d.The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant,confirming the hypothesis that the variant disrupted miRNA binding sites,which led to an increase in IL23R expression and the activation of the PI3K signaling pathway.Furthermore,CAC-induced mice had a significantly higher disease activity index(P<0.05).Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice(P<0.05),reduced the percentage of proliferating cells by 5%,and increased the number of apoptotic cells.The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway,and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.

Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer

In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.

Study on the mechanism of action of Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil in the treatment of colitis-associated colon cancer

Objective:To investigate the therapeutic effects and mechanisms of Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil administration in mice with colitis-associated colon cancer.Methods:To establish a colitis-associated colon cancer mouse model and observe the behavior and activity of mice after Feng-Liao-Chang-Wei-Kang and 5-fluorouracil administration;HE staining to observe the pathological changes of mouse colonic tissue;Western blot was used to detect the expression of mouse colon tissue in IL-6/STAT3 pathway-related proteins.Results:The survival rate of mice in the co-administered group was significantly increased,and the intestinal wall thickening and interstitial inflammation of mice were significantly reduced.Western blot results showed that the expression levels of P-STAT3 and IL-6 were significantly increased in the colonic tissue of mice after modeling,and the combined administration inhibited the expression of Cyclin D1,CDK4 and Bcl-2 protein in the IL-6/STAT3 pathway and upregulated the expression of Bax(P<0.05).Conclusion:Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil inhibits IL-6/STAT3 pathway to exert inhibition of colitis-associated colon cancer inhibition of colitis-associated colon cancer.

Exploring the potential mechanisms of luteolin against ulcerative colitis and colorectal cancer via network pharmacology and molecular docking

Background:Patients diagnosed with ulcerative colitis(UC)are known to have an increased susceptibility to colorectal cancer(CRC).However,the shared underlying mechanisms between UC and CRC remain unclear.Given the therapeutic potential of luteolin in both UC and CRC,this study aims to elucidate the molecular targets and mechanisms through which luteolin exerts its effects against these diseases.Methods:The GeneCards database,DisGENet database,and Gene Expression Omnibus database were utilized to analyze the targets associated with UC and CRC.Subsequently,the Traditional Chinese Medicine Systems Pharmacology and SwissTargetPrediction databases were employed to identify luteolin-related targets.The identified luteolin-related targets were then mapped to official gene symbols using the UniProt database.The Cytoscape 3.9.0 software was utilized to construct a network of luteolin-associated targets.Venn diagram analysis was performed to identify common targets among UC,CRC,and luteolin.The common targets were further analyzed using the STRING database to construct a protein-protein interaction network.The“cytoHubba”plugin in Cytoscape 3.9.0 was employed to identify hub targets within the PPI network.Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were conducted on the hub targets.Finally,molecular docking using AutoDock and PyMOL software was performed to assess the binding affinity between luteolin and the hub targets.Results:Luteolin was found to interact with a total of 149 pharmacological targets,while UC and CRC were associated with 1232 and 3278 targets,respectively.Forty-six common targets were identified among luteolin,UC,and CRC.Through the application of seven different algorithms,seven hub targets were identified,TP53,AKT1,TNF,SRC,EGFR,and MMP9.Bioinformatics enrichment analysis revealed 49 enriched pathways through Kyoto Encyclopedia of Genes and Genomes analysis,while Gene Ontology analysis yielded a total of 245 biological processes,4 cellular components,and 7 molecular functions.Molecular docking simulations demonstrated a good binding affinity between luteolin and the hub targets.Conclusion:This study identified multiple potential pharmacological targets and elucidated various biological pathways through which luteolin may exert its therapeutic effects in the treatment of UC and CRC.These findings provide a solid theoretical foundation for further experimental investigations in the treatment of UC and CRC.